Background Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. Methods LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). Results 1568 participants were randomised during 2007–2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75–1.95) or 0.82 (95% CI 0.52–1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. Conclusions Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.

Low-dose CT screening for lung cancer is effective but expensive. Therefore, cheaper or more focused screening strategies may be required. LungSEARCH is a randomised prospective trial of 1568 high-risk individuals (ie, current or former moderate to heavy smokers with mild/moderate COPD) who undergo either annual sputum cytology/cytometry testing or no screening. Those with abnormal sputum then receive annual CT and fluorescent bronchoscopy for the remainder of 5 years, to identify early stage lung cancer. It is hoped that these simple initial tests could identify those requiring expensive CT scans, and the aim is to demonstrate a stage shift towards early stage cancers.Trial registration numbersISRCTN:ISRCTN80745975, clinicaltrials.gov: NCT00512746.

Dr Oliver Anthony Nasseem Husain, who died on 22 September 2014, aged 90 years, was one of the great names of European cytology, a pioneer of automated cervical screening and a founding member of both the British Society for Clinical Cytology (BSCC) and the European Federation of Cytology Societies (EFCS). The life of this one remarkable man involved much of the pioneering work, which is reviewed in this article, that has brought conventional cytology to the complex multimodal discipline it is today.

Diagnostic Cytopathology Essentials is a succinct yet comprehensive guide to diagnosis in both non-gynecological and gynecological cytology. It provides quick answers to diagnostic problems in the cytological interpretation and recognition of a wide range of disease entities. With content derived from Diagnostic Cytopathology, 3rd Edition, the authoritative reference work by Winifred Gray and Gabrijela Kocjan, Diagnostic Cytopathology Essentials delivers the dependable guidance you need - in a user-friendly format that makes essential facts about any given condition easy to find and apply.

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Ž. P. Marinšek, N. Nolde, I. Kardum‐Skelin, R. Nizzoli, B. Önal, T. Rezanko, E. Tani, K. T. Ostović, P. Vielh, F. Schmitt and G. Kocjan Multinational study of oestrogen and progesterone receptor immunocytochemistry on breast carcinoma fine needle aspiratesObjectives: To collect data on the variability of immunocytochemical (ICC) procedures used to detect oestrogen/progesterone receptors (ER/PR) on cytological material; to test the reproducibility of results; and to identify the crucial points in the ICC procedures that affect the result.Methods: Ten laboratories from eight countries participated in a two‐part study. In the first part, one of the participants (the coordinator) prepared and distributed cytospins from a fine needle aspirate of a primary breast carcinoma. Laboratories performed ICC staining for ER/PR according to their own methods on the test slides and in‐house positive controls. Slides were returned to the coordinator together with information on the preparation of positive control slides and the ICC methodology used. In the second part, obligatory methods of fixation and antigen retrieval were specified. Evaluation of results included grading the number of positive cells, staining intensity, background staining, cytoplasmic staining, sample condition and cellularity. Participants evaluated their own results, which were subsequently evaluated by the coordinator.Results: There was great variability in the preparation of slides for in‐house controls and ICC methodology. The outcome of ICC staining of in‐house control slides was excellent in two laboratories, adequate in three, sub‐optimal in four and inadequate in one. Only six obtained a positive reaction on the test slides and not all were of a high quality. Results of the second run were greatly improved in terms of cellularity of in‐house positive control slides, and scores for the percentage of stained cells and staining intensity of control and test slides. Cytospins and monolayer (ThinPrep®) preparations were superior to direct smears; methods of fixation and antigen retrieval were the key points in the staining process.Conclusions: Our experience points to the need for guidelines for hormonal receptor determination and external quality control on cytological material, in order for cytological methods to be used in routine clinical practice with a suitable degree of confidence.

RATIONALE Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the "gold standard" investigation when a pathological diagnosis is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer. OBJECTIVE To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML. METHODS Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy. MEASUREMENTS AND MAIN RESULTS EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77-94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83-95%) and 40% (95% CI, 12-74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient. CONCLUSIONS EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML. Clinical trial registered with ClinicalTrials.gov (NCT00932854).

The aims of our study were to collect data on the variability of immunocytochemical (ICC) procedures used in estrogen/progesterone (ER/PR) determination on cytological material, to test the reproducibility of results and to determine which procedures influence the outcome of reactions. Ten laboratories from eight countries participated in the study. In the first part, the coordinating laboratory prepared cytospins from an FNA sample of a primary breast carcinoma and distributed them. Participants performed ICC staining for ER/PR according to their own methods on the test slides and on the in-house positive controls. Slides were returned to the coordinator together with the information on the preparation of positive control slides and ICC methodology used. In the second run the preparation and fixation of control slides and antigen retrieval were specified. Evaluation of results included grading the number of positive cells, the intensity of nuclear, background and cytoplasmic staining, sample condition and cellularity of in-house positive control samples. Each participant evaluated their own results, the coordinator evaluated the results from all participants and compared the two evaluations. There was great variability in preparation of slides for in-house controls and in ICC methodology. The outcome of ICC staining of in- house control slides was excellent in two laboratories, adequate in two, sub-optimal in four and inadequate in one. Only six laboratories obtained a positive reaction on the test slides, however, not all of them were of high standard quality. Results of the second run were greatly improved. Cellularity of in-house positive control slides increased while the scores for percentage of stained cells and nuclear staining intensity were higher on the in-house control slides and on the test slides compared to the scores from the first run. There was a great variability at each step of specimen preparation, fixation and ICC staining of hormonal receptors among laboratories. We established that cytospins and monolayer preparations are superior to direct smears and identified the fixation and the antigen retrieval as the key points in the staining process. Inter-laboratory reproducibility of hormonal receptor determination on test slides was not satisfactory. Many laboratories relied on positive in-house controls which were not of optimal quality. Some laboratories were not critical enough as to the outcome of their ICC staining results. Therefore, guidelines for hormonal determination in cytology as well as external quality control are essential.

RATIONALEThe current management of advanced non-small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the subclassification and genotyping of NSCLC.OBJECTIVESTo determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC.METHODSCytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011.MEASUREMENTS AND MAIN RESULTSThe proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73-80). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28-0.82; P = 0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in patients with NSCLC were 88% (95% CI, 86-91), 72% (95% CI, 66-77), and 91% (95% CI, 89-93), respectively.CONCLUSIONSThis large, multicenter, pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for subtyping of NSCLC and EGFR mutation analysis and that the use of immunohistochemistry reduces the rate of NSCLC-NOS.

Background and objective: Standard bronchoscopic techniques (transbronchial lung biopsy and endobronchial biopsy) provide a diagnosis in 70% of patients with pulmonary sarcoidosis. Previous data suggest that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity in patients with sarcoidosis. The feasibility and utility of combining EBUS-TBNA with standard bronchoscopic techniques is unknown. The aim of this study was to evaluate the feasibility, safety and efficacy of combined EBUS-TBNA and standard bronchoscopic techniques in patients with suspected sarcoidosis and enlarged mediastinal or hilar lymphadenopathy.Methods: Forty consecutive patients with suspected pulmonary sarcoidosis and enlarged mediastinal or hilar lymph nodes (radiographical stage I and stage II) underwent EBUS-TBNA followed by transbronchial biopsies and endobronchial biopsies under conscious sedation.Results: Thirty-nine out of 40 patients successfully underwent combined EBUS-TBNA and standard bronchoscopy. Twenty-seven patients were diagnosed with sarcoidosis, eight had tuberculosis, two had reactive lymphadenopathy, two had lymphoma and one had metastatic adenocarcinoma. In patients with sarcoidosis, the sensitivity of EBUS-TBNA for detection of non-caseating granulomas was 85%, compared with a sensitivity of 35% for standard bronchoscopic techniques (P < 0.001). The diagnostic yield of combined EBUS-TBNA and bronchoscopy was 93% (P < 0.0001).Conclusions: Combination of EBUS-TBNA with standard bronchoscopic techniques is safe and feasible, and optimizes the diagnostic yield in patients with pulmonary sarcoidosis and enlarged intrathoracic lymphadenopathy.

CytopathologyVolume 22, Issue 2 p. 139-140 Correspondence The danger to cytopathology of over-specialization and its relevance for histopathology R. Dina, R. Dina Histopathology Department, Imperial College NHS Trust, London, UKSearch for more papers by this authorM. Gudi, M. Gudi Histopathology Department, Imperial College NHS Trust, London, UKSearch for more papers by this authorG. Kocjan, G. Kocjan Department of Cellular Pathology, University College London, UKSearch for more papers by this authorF. Schmitt, F. Schmitt Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalSearch for more papers by this authorP. Vielh, P. Vielh Department of Pathology, Institut Gustave Roussy, Villejuif, FranceSearch for more papers by this author R. Dina, R. Dina Histopathology Department, Imperial College NHS Trust, London, UKSearch for more papers by this authorM. Gudi, M. Gudi Histopathology Department, Imperial College NHS Trust, London, UKSearch for more papers by this authorG. Kocjan, G. Kocjan Department of Cellular Pathology, University College London, UKSearch for more papers by this authorF. Schmitt, F. Schmitt Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalSearch for more papers by this authorP. Vielh, P. Vielh Department of Pathology, Institut Gustave Roussy, Villejuif, FranceSearch for more papers by this author First published: 23 March 2011 https://doi.org/10.1111/j.1365-2303.2011.00865.xCitations: 5 R. Dina, Histopathology Department, Hammersmith Hospital, Du Cane Road, Imperial College NHS Trust, London W12 0HS, UKTel.: +44-20-3313-2444; Fax: +44-20-3313-2215; E-mail: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume22, Issue2April 2011Pages 139-140 RelatedInformation

C. Lobo, S. Amin, A. Ramsay, T. Diss and G. KocjanSerous fluid cytology of multicentric Castlemans disease and other lymphoproliferative disorders associated with Kaposi sarcoma-associated herpes virus: a review with case reportsObjective: The aim of this study is to describe and review the cytological features of Kaposi sarcoma-associated herpes virus (KSHV) related entities, such as multicentric Castleman's disease (MCD), plasmablastic-lymphoma (PBL) and primary effusion lymphoma (PEL), which all may present as body cavity effusions. Serous fluid cytology of MCD and PBL has not, to our knowledge, thus far been described. Although different in nature, MCD, PBL and PEL are characterized by similar morphological features.Materials and methods: Body cavity effusions from four different patients with previously known or unknown KSHV-related lymphoproliferations have been examined by routine cytology, immunocytochemistry (IC) and polymerase chain reaction (PCR).Results: MCD, PBL and PEL are all characterized by increased cellularity, comprising mainly lymphoid and plasmacytoid cells with variable proportions of immunoblasts. Immunocytochemistry and PCR results show the MCD to be CD138 and KSHV positive, CD30 negative, IgM, IgH and lambda restricted but IgH polyclonal. PBL was CD138 positive, kappa restricted, weakly positive with VS38 and over 80% positive with MIB 1. PEL was CD45, EMA, CD138, KSHV, p53 and CD3 positive, CD20, EBV, CD30, CD2, CD4, ALK1, epithelial and mesothelial markers negative, and PCR monoclonal B-cell expanded (Ig-kappa bands).Conclusion: Cytological examination of effusions in KSHV-related lymphoproliferative disorders may show similar morphological features but clonality studies and immunocytochemistry are very helpful in distinguishing between these rare benign and malignant lymphoproliferative diseases.